COMBINATION THERAPY OF ANTI-TAU AND ANTI-AMYLOID DRUGS FOR DISEASE MODIFICATION IN EARLY-STAGE ALZHEIMER’S DISEASE: SOCIO-ECONOMIC CONSIDERATIONS MODELED ON TREATMENTS FOR TUBERCULOSIS, HIV/AIDS AND BREAST CANCER

Current drugs for treatment of mild to severe dementia of the Alzheimer’s type include cholinesterase inhibitors and the NMDA non-competitive receptor antagonist memantine. There is controversy as to the additive benefit of these symptomatic drugs, and their effects are clinically modest. Patients with Alzheimer’s disease (AD) are known to have characteristic pathology, including senile plaques with amyloid beta-protein aggregates and neurofibrillary tangles with assembled tau proteins, which start in the hippocampus and spread to neighboring areas. Amyloid and tau modifying drugs are under clinical testing. Based on this pathophysiology, it is crucial to investigate whether anti-amyloid and anti-tau combined therapy would show efficacy in early stage of AD, beyond what could be achieved with anti-amyloid or anti-tau monotherapy. It is equally important to consider the socio-economic implications of such a combination therapy, if effective. We hypothesize that the high costs of combination therapy for early-stage AD patients will require societal and public health initiatives to ensure universal access to AD treatment. In order to better predict these socio-economic implications, we summarize the management of other combination therapies used for tuberculosis, HIV/AIDS, and breast cancer, based on a database search of PubMed and other relevant sources. We put forward a framework for testing a potential anti-amyloid and anti-tau disease modifying combination therapy for early-stage AD patients and present an analysis of the socio-economic implications of such a combination therapy.

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Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer’s Disease

Molecules ◽

10.3390/molecules25061267 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1267 ◽

Cited By ~ 20

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Kamal Niaz ◽

Philippe Jeandet ◽

Christophe Clément ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Senile Plaques ◽

Symptomatic Relief ◽

Point Of View ◽

Tau Proteins ◽

Experimental Proof ◽

Aβ Peptides ◽

Inhibitory Potential

Alzheimer’s disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer’s pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

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Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E

Biochemical Journal ◽

10.1042/bj3060599 ◽

1995 ◽

Vol 306 (2) ◽

pp. 599-604 ◽

Cited By ~ 152

Author(s):

E M Castano ◽

F Prelli ◽

T Wisniewski ◽

A Golabek ◽

R A Kumar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Late Onset ◽

Senile Plaques ◽

Amyloid Β ◽

Fibril Formation ◽

Tau Proteins ◽

Amyloid Formation

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

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Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00988-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Shan-Shan Wang ◽

Zi-Kai Liu ◽

Jing-Jing Liu ◽

Qing Cheng ◽

Yan-Xia Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Senile Plaques ◽

Disease Stage ◽

Assay Method ◽

Imaging Probe ◽

Asparaginyl Endopeptidase ◽

Potential Biomarker ◽

The Brain

Abstract Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

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Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms23010345 ◽

2021 ◽

Vol 23 (1) ◽

pp. 345

Author(s):

Yaping Liu ◽

Runrong Ding ◽

Ze Xu ◽

Yuan Xue ◽

Dongdong Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quality Control ◽

Control System ◽

Protein Quality ◽

Early Stage ◽

Senile Plaques ◽

Protein Quality Control ◽

Quality Control System ◽

Protein Quality Control System

Alzheimer’s disease (AD) is characterized by the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs), as well as neuronal dysfunctions in the brain, but in fact, patients have shown a sustained disease progression for at least 10 to 15 years before these pathologic biomarkers can be detected. Consequently, as the most common chronic neurological disease in the elderly, the challenge of AD treatment is that it is short of effective biomarkers for early diagnosis. The protein quality control system is a collection of cellular pathways that can recognize damaged proteins and thereby modulate their turnover. Abundant evidence indicates that the accumulation of abnormal proteins in AD is closely related to the dysfunction of the protein quality control system. In particular, it is the synthesis, degradation, and removal of essential biological components that have already changed in the early stage of AD, which further encourages us to pay more attention to the protein quality control system. The review mainly focuses on the endoplasmic reticulum system (ERS), autophagy–lysosome system (ALS) and the ubiquitin–proteasome system (UPS), and deeply discusses the relationship between the protein quality control system and the abnormal proteins of AD, which can not only help us to understand how and why the complex regulatory system becomes malfunctional during AD progression, but also provide more novel therapeutic strategies to prevent the development of AD.

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Anti-Neuroinflammatory Potential of Polyphenols by Inhibiting NF-κB to Halt Alzheimer's Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666201118092422 ◽

2020 ◽

Vol 26 ◽

Author(s):

Md. Sahab Uddin ◽

Sharifa Hasana ◽

Jamil Ahmad ◽

Md. Farhad Hossain ◽

Md. Mosiqur Rahman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Amyloid Β ◽

Neuronal Loss ◽

Research Area ◽

Tau Proteins ◽

Brain Disorder ◽

Drug Candidates ◽

Life Threatening

: Alzheimer's disease (AD) is an irrevocable chronic brain disorder featured by neuronal loss, microglial accumulation, and progressive cognitive impairment. The proper pathophysiology of this life-threatening disorder is not completely understood and no exact remedies are found yet. Over the last few decades, research on AD has mainly highlighted in pathomechanisms linked to a couple of the major pathological hallmarks, including extracellular senile plaques, made of amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs), made of tau proteins. Aβ can induce apoptosis, trigger an inflammatory response, and inhibit the synaptic plasticity of the hippocampus, which ultimately contributes to reducing cognitive functions and memory impairment. Recently, a third disease hallmark, the neuroinflammatory reaction that is mediated by cerebral innate immune cells, has become a spotlight in the current research area, assured by pre-clinical, clinical, and genetic investigations. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a cytokine producer, is significantly associated with physiological inflammatory proceedings and thus showing a promising candidate for inflammation-based AD therapy. Recent data reveal that phytochemicals mainly polyphenols compounds exhibit potential neuroprotective functions and it may be considered as a vital resource for discovering several drug candidates against AD. Interestingly, phytochemicals can easily interfere with the signaling pathway of NF-κB. This review represents the anti-neuroinflammatory potential of polyphenols as inhibitors of NF-κB to combat AD pathogenesis.

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Antioxidant Therapies for Alzheimer's Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/472932 ◽

2012 ◽

Vol 2012 ◽

pp. 1-17 ◽

Cited By ~ 146

Author(s):

Ye Feng ◽

Xiaochuan Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Senile Plaques ◽

Toxic Substances ◽

Synaptic Loss ◽

Recent Developments ◽

Multiple Cell ◽

Future Potential ◽

And Behavior

Alzheimer’s disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes of Alzheimer’s disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer’s disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer’s disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer’s disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases.

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Involvement of Cholinergic, Adrenergic, and Glutamatergic Network Modulation with Cognitive Dysfunction in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22052283 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2283

Author(s):

Yu-Jung Cheng ◽

Chieh-Hsin Lin ◽

Hsien-Yuan Lane

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Early Stage ◽

Amyloid Β ◽

Tau Proteins ◽

And Oxidative Stress

Alzheimer’s disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. The number of AD cases has been rapidly growing worldwide. Several the related etiological hypotheses include atypical amyloid β (Aβ) deposition, neurofibrillary tangles of tau proteins inside neurons, disturbed neurotransmission, inflammation, and oxidative stress. During AD progression, aberrations in neurotransmission cause cognitive decline—the main symptom of AD. Here, we review the aberrant neurotransmission systems, including cholinergic, adrenergic, and glutamatergic network, and the interactions among these systems as they pertain to AD. We also discuss the key role of N-methyl-d-aspartate receptor (NMDAR) dysfunction in AD-associated cognitive impairment. Furthermore, we summarize the results of recent studies indicating that increasing glutamatergic neurotransmission through the alteration of NMDARs shows potential for treating cognitive decline in mild cognitive impairment or early stage AD. Future studies on the long-term efficiency of NMDA-enhancing strategies in the treatment of AD are warranted.

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Nutraceuticals and their Derived Nano-formulations for the Prevention and Treatment of Alzheimer's disease

Current Molecular Pharmacology ◽

10.2174/1874467214666210309115605 ◽

2021 ◽

Vol 14 ◽

Author(s):

Ashif Iqubal ◽

Mohammad Kashif Iqubal ◽

Syed Abul Fazal ◽

Faheem Hyder Pottoo ◽

Syed Ehtaishamul Haque

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Particle Size ◽

Senile Plaques ◽

Neurofibrillary Tangle ◽

Hepatic Metabolism ◽

Tau Proteins ◽

Nitrative Stress ◽

Effective Delivery ◽

The Brain

: Alzheimer’s disease is one of the common chronic neurological disorders and associated with cognitive dysfunction, depression and progressive dementia. Presence of β-amyloid or senile plaques, hyper-phosphorylated tau proteins, neurofibrillary tangle, oxidative-nitrative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation and derailed neurotransmitter status are the hallmark of AD. Currently, donepezil, memantine, rivastigmine and galantamine are approved by the FDA for symptomatic management. It is well-known that these approved drugs only exert symptomatic relief and possess poor patient-compliance. Additionally, various published evidence shows the neuroprotective potential of various nutraceuticals via their antioxidant, anti-inflammatory and anti-apoptotic effects in the preclinical and clinical studies. These nutraceuticals possess a significant neuroprotective potential and hence, can be a future pharmacotherapeutic for the management and treatment of AD. However, nutraceutical suffers from certain major limitations such as poor solubility, low bioavailability, low stability, fast hepatic-metabolism and larger particle size. These pharmacokinetic attributes restrict their entry into the brain via the blood-brain barrier. Therefore, to over such issues, various nanoformulation of nutraceuticals was developed, that allows their effective delivery into brain owning to reduced particle size, increased lipophilicity increased bioavailability and avoidance of fast hepatic metabolism. Thus, in this review, we have discussed the etiology of AD, focused on the pharmacotherapeutics of nutraceuticals with preclinical and clinical evidence, discussed pharmaceutical limitation and regulatory aspects of nutraceuticals to ensure safety and efficacy. We further explored the latitude of various nanoformulation of nutraceuticals as a novel approach to overcome the existing pharmaceutical limitation and for effective delivery into the brain.

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Current Biomarkers for Alzheimer’s Disease: From CSF to Blood

Journal of Personalized Medicine ◽

10.3390/jpm10030085 ◽

2020 ◽

Vol 10 (3) ◽

pp. 85 ◽

Cited By ~ 1

Author(s):

Kun Zou ◽

Mohammad Abdullah ◽

Makoto Michikawa

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Early Stage ◽

Biological Fluid ◽

Amyloid Β ◽

Positron Emission Tomography Imaging ◽

Tau Proteins ◽

Csf Biomarkers ◽

Amyloid Β Protein

Alzheimer’s disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, a diagnosis of AD depends on the clinical symptoms of dementia, magnetic resonance imaging to determine brain volume, and positron emission tomography imaging to detect brain amyloid or tau deposition. The best characterized biological fluid markers for AD are decreased levels of amyloid β-protein (Aβ) 42 and increased levels of phosphorylated tau and total tau in cerebrospinal fluid (CSF). However, less invasive and easily detectable biomarkers for the diagnosis of AD, especially at the early stage, are still under development. Here, we provide an overview of various biomarkers identified in CSF and blood for the diagnostics of AD over the last 25 years. CSF biomarkers that reflect the three hallmarks of AD, amyloid deposition, neurofibrillary tangles, and neurodegeneration, are well established. Based on the need to start treatment in asymptomatic people with AD and to screen for AD risk in large numbers of young, healthy individuals, the development of biomarkers for AD is shifting from CSF to blood. Elements of the core pathogenesis of AD in blood, including Aβ42, tau proteins, plasma proteins, or lipids have shown their usefulness and capabilities in AD diagnosis. We also highlight some novel identified blood biomarkers (including Aβ42/Aβ43, p-tau 181, Aβ42/APP669-711, structure of Aβ in blood, and flotillin) for AD.

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Oxidative Stress and the Pathogenesis of Alzheimer's Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/316523 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 248

Author(s):

Yan Zhao ◽

Baolu Zhao

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Neuronal Loss ◽

The Elderly ◽

Redox Balance ◽

Tau Proteins ◽

Molecular Events ◽

Abnormal Accumulation

Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. Patients with AD suffer a gradual deterioration of memory and other cognitive functions, which eventually leads to a complete incapacity and death. A complicated array of molecular events has been implicated in the pathogenesis of AD. The major pathological characteristics of AD brains are the presence of senile plaques, neurofibrillary tangles, and neuronal loss. Growing evidence has demonstrated that oxidative stress is an important factor contributing to the initiation and progression of AD. However, the mechanisms that lead to the disruption of redox balance and the sources of free radicals remain elusive. The excessive reactive oxygen species may be generated from mechanisms such as mitochondria dysfunction and/or aberrant accumulation of transition metals, while the abnormal accumulation of Abeta and tau proteins appears to promote the redox imbalance. The resulted oxidative stress has been implicated in Abeta- or tau-induced neurotoxicity. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Abeta and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD.

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